Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases

Figures & data

Figure 1 The role of DCA in metabolism.

Notes: DCA enhances PDH indirectly by inhibiting PDK, thereby enhancing mitochondrial oxidation of glucose. Created with BioRender.com.

Abbreviations: DCA, dichloroacetate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; TCA, tricarboxylic acid.

Table 1 Neuroprotective effects of Dichloroacetate

Disease	Bioactivity	Mechanism	Animals	The Dosage of DCA	References
Ischaemic Stroke, Perinatal Asphyxia-induced Hypoxic Ischaemic Brain Injury, Transient Ischaemia, Cardiac Arrest Brain Injury	Improve metabolism	Enhance PDH activity, increase adenosine triphosphate and creatine phosphate content in the brain, reduce lactate	Male SD rats	DCA (100 mg/kg i.v.), 30 min before ischaemia, 60 min after ischaemia during reperfusion	[32]
			Male Mongolian gerbils	DCA (2.3 mmol/kg i.p.), 30 min before ischaemia	[33]
			Male SD rats	DCA (5 ml/ kg i.v), 15 min before ischaemia or 1 hour after ischaemia	[34]
			Male rats	DCA (50 mg/kg)	[35]
			Male rats	DCA (100 mg/kg or I0 mg/kg i.v.), 10 min before ischaemia	[36]
			Male C57BL/6 mice	DCA (100 or 200 mg/kg), 60 min after ischaemia during reperfusion	[37]
			Human Brain Microvascular Endothelial Cells	DCA (2.5 or 5 or 10mmol/L) pretreatment for 6h
			Male rats	DCA (100 mg/kg/d for two days i.p.), after reperfusion	[38]
			Male mice	DCA (100 mg/kg/d for three days i.p.), after hypoxia-ischaemia	[39]
			Brain-derived Endothelial cells (bEnd3)	DCA (30 μmol/L) pretreatment for 12h	[40]
	Anti-oxidant	Up-regulation Nrf2 signaling pathway	ibid.		[37]
			ibid.		[38]
	Anti-neuroinflammatory	Reduce glial cells activation and production of inflammatory factors (tumor necrosis factor α and interleukin-1β)	ibid.		[38]
		Upregulate CD206, downregulated inducible nitric oxide synthase and interleukin-6	Male SD rats	DCA (14.4 mg/kg), after the model was established for 2, 4 and 24h	[40]
			Primary mouse microglia	DCA (30 μmol/L) pretreatment for 3h
	Anti-apoptosis	Inhibit apoptosis-inducing factor and Caspase-3 activation	ibid.		[37,39]
	Reduce autophagy	Prevent the reduction of Sequestosome 1	ibid.		[39]
	Improve mitochondrial dynamics	Increase Pgc-1α and nuclear respiratory factor 1 mRNA, but not mitochondrial DNA	ibid.		[39]
	Protect the BBB	Enhance the expression of Zonula Occludens Protein 1 and Occludin	ibid.		[37,38]
Subarachnoid Hemorrhage	Aggravate oxidative stress and Neuronal death	Inhibit the activity of PDK4, activate reactive oxygen species- apoptosis signal-regulating kinase 1/ mitogen-activated protein kinase pathway	Male SD rats	DCA (100mg/kg/d for two days i.p.)	[41]
			Primary neurons	DCA (50 μmol/L) pretreatment for 2 days.
Vascular Dementia	Promote angiogenesis and improve endothelial progenitor cell function	Increase protein kinase B expression, decrease glycogen synthase kinase 3β expression	Male rats	DCA (50 or 100 or 200 mg/kg for 21 days i.g.), 24h after reperfusion	[42]
	Anti-oxidant	Activate Nrf2 pathway
Hypoglycemic Brain Injury	Improve metabolism	Reduce the level of PDK2, increase the level of PDH, reduce microglia and astrocyte Activation	Male rats	DCA (100 mg/kg/d for two days i.v.), after hypoglycemia	[43]
	Anti-oxidant
	Anti-neuroinflammatory
	Protect the BBB
Traumatic Brain Injury	Improve metabolism	Enhance PDH activity, reduce lactate accumulation, no evaluation of the effects of DCA on brain damage	Male rats	DCA (200 mg/kg i.v.), after traumatic brain injury	[44]
Epilepsy	Improve metabolism	Reduce the level of PDK2, increase the level of PDH, reduce microglia and astrocyte activation	Male CD1 mice	DCA (50 mg/kg/day for 7 days) in drinking water before seizures; DCA (100 mg/kg/day for 14 days) after seizures	[45]
			Male rats	DCA (100 mg/kg/d for one week)	[46]
	Anti-oxidant
	Anti-neuroinflammatory
Amyotrophic Lateral Sclerosis	Reduce toxicity of aberrant glial cells	Improve mitochondrial metabolism, enhance PDH activity, reduce lactate	SOD1^G93A mice	DCA (100 mg/kg/d), add to drinking water, from 70 days old to death	[47]
			AbGCs (derived from SOD1^G93A rats)	DCA (0.5–5 mmol/L) pretreatment for 24h
			Female SOD1^G93A rats	DCA (100mg/kg/d for 10 days), add to the drinking water	[48]
			AbGCs (isolated from the spinal cords of adult paralytic SOD1^G93A rats)	DCA (5 mmol/L) pretreatment for 24h
	Modify metabolism in glycolytic muscles	Reduce the level of PDK4, enhance PDH activity, promote glycolysis and inhibit, inhibit fatty acid β-oxidation, increase Pgc1-α and mitochondrial fusion protein 2 levels	Male SOD1^G86R mice	DCA (500 mg/kg/d), add to drinking water, from 60 to 95 days of age	[49]
	Anti-oxidant
	Improve mitochondrial dynamics
Alzheimer’s Disease	Reduce amyloid β-protein production	Inhibit amyloidogenic proteolysis of the amyloid precursor protein	Human neuroblastoma cells (SH-SY5Y)	DCA (10 or 20 mmol/L for 24h)	[50]
Huntington’s Disease	Alleviate the striatal volume reduction	Enhance PDH activity	N171/82Q mice, R6/2 mice	DCA (100mg/kg/d), add to drinking water, from 4 weeks of age to death	[51]
Parkinson’s Disease	Improve mitochondrial dynamics	Improve mitochondrial metabolism	Rat pheochromocytoma cells (PC12)	DCA (10mmol/L for 1h)	[52]

Abbreviations: PDH, pyruvate dehydrogenase; Nrf2, nuclear factor; PDK, pyruvate dehydrogenase kinase; PGC1-α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; BBB, blood-brain barrier; i.v., intravenous injection; i.p., intraperitoneal injection; i.g., gastric lavage.

Figure 2 The role of DCA in cerebral ischaemia-reperfusion injury.

Notes: When there is ischaemia-reperfusion injury, ATP deficiency causes the cell membrane ion pump to malfunction and intracellular calcium levels to rise. This triggers the calcium-dependent protease, which in turn catalyzes a sequence of events that result in a significant production of reactive oxygen species. Still, the breakdown of AMP results in the inability to produce new ATP, which causes hydrogen ions to build up in the mitochondrial membrane gap. Similarly, the overabundance of succinate during ischaemia causes the overreduction of CoQ during reperfusion, which causes reverse electron transfer to produce reactive oxygen species. Through the inhibition of PDK activity, DCA regulates mitochondrial metabolism and reduces ROS resulting from reverse electron transfer and ATP deficit. Furthermore, via triggering the Nrf2 pathway, DCA suppresses ROS and lessens ROS-induced cellular autophagy, apoptosis, inflammation, and BBB degradation. Created with BioRender.com.

Abbreviations: DCA, dichloroacetate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; TCA, tricarboxylic acid; XD, xanthine dehydrogenase; XO, xanthine oxidase; Nrf2, nuclear factor erythroid 2-related factor 2; ATP, adenosine triphosphate; ADP, adenosine diphosphate; ROS, reactive oxygen species; AMP, adenosine monophosphate; NADH, reduced nicotinamide adenine dinucleotide; ZO-1, zonula occludens-1; TNF-α, tumor necrosis factor; IL-1, interleukin-1; AIF, apoptosis-inducing factor.

Figure 3 DCA attenuates neuronal death in ALS by targeting AbGCs and glycolytic muscles.

Notes: In AbGCs, DCA increased PDH activity to cause a change in cellular metabolism to mitochondrial metabolism. This prevented lactate from being harmful to neurons and decreased the amount of lactate produced. Furthermore, DCA stimulated the disrupted electron transport chain in the mitochondria of AbGCs, which raised the degree of oxidative stress and prevented AbGC development. When cellular metabolism is disrupted in glycolytic muscles, fatty acids β oxidation provides cells with additional energy. This process activates PPARβ/δ with FOXO1 and inhibits PDH. By increasing PDH activity, DCA lessens the inhibition of glycolysis caused by pyruvate accumulation and increases energy availability, which lowers the metabolism of fatty acids and the generation of reactive oxygen species. Created with BioRender.com.

Abbreviations: DCA, dichloroacetate; PDH, pyruvate dehydrogenase; SOD1, superoxide dismutase 1; ROS, reactive oxygen species; FAs, fatty acids; PFK1, phosphofructokinase 1; PDK, pyruvate dehydrogenase kinase; FOXO1, forkhead box protein O1; PPARβ/δ, peroxisome proliferators-activated receptors β/δ.

Figure 4 Possible mechanisms of neuroprotective effects of Dichloroacetate.

Notes: DCA inhibits PDK activity, thus enhancing PDH activity. This allows more glucose to enter the mitochondria for oxidation and reduces fatty acids β-oxidation, which corrects the disturbance of energy metabolism and reduces oxidative stress caused by insufficient ATP production. DCA exerts protective effects by attenuating multiple damages caused by oxidative stress, including: attenuating excessive autophagy, attenuating neuroinflammation, protecting the BBB, and attenuating apoptosis. DCA may increase the intracellular NAD/NADH AMP/ATP ratio by regulating metabolism and thus activating PGC-1α. Activation of PGC-1α has multiple protective effects including: attenuating oxidative stress by activating Nrf2, decreasing the release of inflammatory factors (TNFα, IL-1β), attenuating caspase 3 and AIF-mediated apoptosis, activating Mfn2 and Nrf1 to improve mitochondrial dynamics, and inhibiting BACE1 to reduce Aβ production. Created with BioRender.com.

Abbreviations: DCA, dichloroacetate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PFK1, phosphofructokinase 1; PPARβ/δ, nuclear hormone receptor peroxisome proliferator-activated receptor β/δ; FOXO1, forkhead box transcription factor O1; TCA, tricarboxylic acid; ROS, reactive oxygen species; NAD, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; AMP, adenosine monophosphate; ATP, adenosine triphosphate; SIRT1, sirtuin 1; AMPK, AMP-activated protein kinase; PGC1-α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Nrf2, nuclear factor erythroid 2-related factor 2; ZO-1, zonula occludens protein 1; BBB, blood-brain barrier; TNFα, tumor necrosis factor α; IL-1β, interleukin-1β; AIF, apoptosis-inducing factor; Mfn2, mitochondrial fusion protein 2; Nrf1, nuclear respiratory factor 1; BACE1, β-site amyloid precursor protein cleavage enzyme; Aβ, amyloid β-protein.

Figure 5 Metabolism of DCA and related neurotoxic products.

Note: Created with BioRender.com.

Abbreviations: DCA, dichloroacetate; GSTZ1, glutathione transferase zeta 1; GSH, glutathione; δ-ALA, δ-aminolevulinic acid; FAH, fumarylacetoacetate hydrolase; LDH, lactate dehydrogenase.

Chang LH, Shimizu H, Abiko H, et al. Effect of dichloroacetate on recovery of brain lactate, phosphorus energy metabolites, and glutamate during reperfusion after complete cerebral ischemia in rats. J Cereb Blood Flow Metab. 1992;12(6):1030–1038. doi:10.1038/jcbfm.1992.140

 PubMed Web of Science ®Google Scholar

Katayama Y, Welsh FA. Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain. J Neurochem. 1989;52(6):1817–1822. doi:10.1111/j.1471-4159.1989.tb07262.x

 PubMed Web of Science ®Google Scholar

Peng J, Huang H, Wang F. 二氯醋酸钠对缺血再灌注大鼠脑保护作用的观察 [The protective effects of dichloroacetate on cerebral ischemia after reperfusion of fed rats]. Zhonghua Yi Xue Za Zhi. 1996;76(7):509–511. Chinese.

 PubMedGoogle Scholar

Hu CL. Treatment of experimental ischemic cerebral lactic acidosis in rats with dichloroacetate. Chin J Neurol Psychiatry. 1992;25(6):355.

 Google Scholar

Peeling J, Sutherland G, Brown RA, Curry S. Protective effect of dichloroacetate in a rat model of forebrain ischemia. Neurosci Lett. 1996;208(1):21–24. doi:10.1016/0304-3940(96)12542-8

 PubMed Web of Science ®Google Scholar

Zhao X, Li S, Mo Y, et al. DCA Protects against Oxidation Injury Attributed to Cerebral Ischemia-Reperfusion by Regulating Glycolysis through PDK2-PDH-Nrf2 Axis. Oxid Med Cell Longev. 2021;2021:5173035. doi:10.1155/2021/5173035

 PubMed Web of Science ®Google Scholar

Hong DK, Kho AR, Choi BY, et al. Combined treatment with Dichloroacetic acid and pyruvate reduces hippocampal neuronal death after transient cerebral ischemia. Front Neurol. 2018;9:137.

 PubMed Web of Science ®Google Scholar

Sun Y, Li T, Xie C, et al. Dichloroacetate treatment improves mitochondrial metabolism and reduces brain injury in neonatal mice. Oncotarget. 2016;7(22):31708–31722. doi:10.18632/oncotarget.9150

 PubMedGoogle Scholar

Guan X, Wei D, Liang Z, et al. FDCA Attenuates Neuroinflammation and Brain Injury after Cerebral Ischemic Stroke. ACS Chem Neurosci. 2023;14(20):3839–3854. doi:10.1021/acschemneuro.3c00456

 PubMed Web of Science ®Google Scholar

Gao X, Gao YY, Yan HY, et al. PDK4 decrease neuronal apoptosis via inhibiting ROS-ASK1/P38 pathway in early brain injury after subarachnoid hemorrhage. Antioxid Redox Signal. 2022;36(7–9):505–524. doi:10.1089/ars.2021.0083

 PubMed Web of Science ®Google Scholar

Zhao H, Mao J, Yuan Y, et al. Sodium Dichloroacetate stimulates angiogenesis by improving endothelial precursor cell function in an AKT/GSK-3beta/Nrf2 dependent pathway in vascular dementia rats. Front Pharmacol. 2019;10:523. doi:10.3389/fphar.2019.00523

 PubMed Web of Science ®Google Scholar

Kho AR, Choi BY, Lee SH, et al. The Effects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury. Cells. 2019;8(5):405. doi:10.3390/cells8050405

 PubMed Web of Science ®Google Scholar

DeVience SJ, Lu X, Proctor JL, et al. Enhancing Metabolic Imaging of Energy Metabolism in Traumatic Brain Injury Using Hyperpolarized [1-(13)C]Pyruvate and Dichloroacetate. Metabolites. 2021;11(6):335. doi:10.3390/metabo11060335

 PubMed Web of Science ®Google Scholar

Durie D, McDonald TS, Borges K. The effect of dichloroacetate in mouse models of epilepsy. Epilepsy Res. 2018;145:77–81. doi:10.1016/j.eplepsyres.2018.06.004

 PubMed Web of Science ®Google Scholar

Lee SH, Choi BY, Kho AR, et al. Combined treatment of dichloroacetic acid and pyruvate increased neuronal survival after seizure. Nutrients. 2022;14(22):4804. doi:10.3390/nu14224804

 PubMed Web of Science ®Google Scholar

Miquel E, Cassina A, Martinez-Palma L, et al. Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis. PLoS One. 2012;7(4):e34776. doi:10.1371/journal.pone.0034776

 PubMed Web of Science ®Google Scholar

Martinez-Palma L, Miquel E, Lagos-Rodriguez V, Barbeito L, Cassina A, Cassina P. Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis. Neurotherapeutics. 2019;16(1):203–215. doi:10.1007/s13311-018-0659-7

 PubMed Web of Science ®Google Scholar

Palamiuc L, Schlagowski A, Ngo ST, et al. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. 2015;7(5):526–546. doi:10.15252/emmm.201404433

 PubMed Web of Science ®Google Scholar

Parkin ET, Hammond JE, Owens L, Hodges MD. The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein. PLoS One. 2022;17(1):e0255715. doi:10.1371/journal.pone.0255715

 PubMed Web of Science ®Google Scholar

Andreassen OA, Ferrante RJ, Huang HM, et al. Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington’s disease. Ann Neurol. 2001;50(1):112–117. doi:10.1002/ana.1085

 PubMed Web of Science ®Google Scholar

O’Hara D, Davis GM, Adlesic NA, Hayes JM, Davey GP. Dichloroacetate Stabilizes Mitochondrial Fusion Dynamics in Models of Neurodegeneration. Front Mol Neurosci. 2019;12:219. doi:10.3389/fnmol.2019.00219

 PubMed Web of Science ®Google Scholar